Association Testing in a Linked Region Using Large Pedigrees

Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095-7088, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2005; 76(3):538-42. DOI: 10.1086/428628
Source: PubMed


This report describes computer implementation of a scheme for joint linkage and association analysis. The model implemented in the computer package Mendel estimates both recombination and linkage-disequilibrium parameters and conducts likelihood-ratio tests for (1) linkage alone, (2) linkage and association simultaneously, and (3) association in the presence of linkage. Application of the method to data from Finnish pedigrees with familial combined hyperlipidemia illustrates its potential for identification of associated SNP haplotypes in the presence of linkage. For the test results to be valid, good estimates of haplotype frequencies must be used in the analysis.

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Available from: Gary K Chen, Oct 16, 2014
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    • "For a review and comparison of different secondary sample approaches, see Glaser and Holmans (2009) and Infante-Rivard et al. (2009). Alternatively, it is possible to analyse these two samples (with association and linkage) separately and study the overlap between the results (Manenti et al., 2009), or carry out association testing conditionally on the linkage results (Cantor et al., 2005). As the use of secondary samples to correct for population stratification relies on two separate samples, issues relating to the presence of heterogeneity cannot be fully ruled out (see Sillanpää and Auranen, 2004). "
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    • "However, a stepwise strategy, where linkage analysis is carried out first, and then association analysis is employed conditionally on the results of the preliminary linkage analysis, is possible, especially in population isolates. Such a strategy is also the motivation behind the methods that detect associations in the presence of linkage signals (Cantor et al. 2005). It could also be possible to treat several tightly linked SNPs as a single multiallelic locus, if credible haplotype information were available. "
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    • "Multipoint linkage analysis with selected markers was performed using SimWalk2 based on the genetic position in the recombination maps generated by HapMap. Association analysis suitable for the pedigrees was conducted using the association given linkage option in Mendel [Cantor et al., 2005] using the same allele frequency estimates as for linkage analysis. A two-point test of association was performed using Transmit [Clayton, 1999] for both duos and trios. "
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